JOURNAL OF GASTROENTEROLOGY
·
2025
·
IF 5.5
Ren Bingyu,Li Han,Liu Shenglu,Huang Zhiwei,Bai Junjie,Jiang Zhonghao,Xu Tongjie,Gu Boyuan,Yu Wenhao,Sun Lei,Tan Peng,Fu Wenguang
Background and Aims Inflammatory cell infiltration in the liver is a hallmark of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the pathological events that trigger the infiltration of inflammatory cells to mediate MAFLD pathogenesis remains poorly understood. This study aims to investigate the function and mechanism of Hic-5 on hepatic inflammation of MAFLD. Methods MAFLD animal models were fed a methionine- and choline-deficient (MCD) diet in Hic-5 knockout mice. Liver tissues were analyzed by immunohistochemical staining, immunofluorescence and flow cytometry, with a particular focus on the impact on the immune microenvironment. Results Hic-5 deficiency alleviates the severity of MAFLD, particularly the inflammation response. Gain- and loss-of-function experiments revealed that Hic-5 deficiency results in decreased neutrophil proliferation and increased apoptosis, as well as impaired migration. Conversely, Hic-5 overexpression had the opposite effects. This study confirmed that METTL3-mediated methylation of m 6 A stabilizes Hic-5 mRNA and promotes its expression, which in turn regulates the infiltration of neutrophils by the CXCL1-CXCR2 axis. Conclusions The study reveals the role of Hic-5 in regulating neutrophils and indicates that it may be a potential therapeutic target for MAFLD.
研究领域:
肝病学
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免疫学
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分子生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 20
·11061-11069
·
IF 2.936
Jin-Xin Che,Zhi-Long Wang,Xiao-Wu Dong,You-Hong Hu,Xin Xie,Yong-Zhou Hu
CXCR1 and CXCR2 are CXC chemokine receptors (CXCRs), corresponding to cytokines of the CXC chemokine family. CXCR2 was found to be 77% homologous to CXCR1. Antagonism of the chemokine receptor CXCR2 has been proposed as a new strategy for the treatment of metastatic cancer. In order to find a CXCR2 selective antagonist, a bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide (compound 2e) was identified by introducing a bridge ring system into the N,N′-diarylsquaramide skeleton, and it exhibited good CXCR2 antagonistic activity (CXCR2IC50 = 48 nM) and good selectivity (CXCR1IC50/CXCR2IC50 = 60.4). Furthermore, an in vitro biological assay of compound 2e also demonstrated its good anti-cancer metastatic effect against the pancreatic cancer cell line CFPAC1. In addition, compound 2e showed an extremely high stability in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF), as well as in rat and human plasma, but not in rat and human liver microsomes. In vivo pharmacokinetic studies in rats indicated that 2e has an excellent PK profile (10 mg kg−1 po, Cmax = 2863 ng mL−1, t1/2 = 2.58 h). Moreover, molecular docking was further implemented to propose the preponderant configuration of compound 2e, providing important and useful guidelines for further development.
研究领域:
肿瘤学
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药理学
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化学
✓ 已验证
DOI
高影响因子
Theranostics
·
2025
·Vol. 15
·期 16
·8488
·
IF 13.3
Jiyuan Chen,Luyao Gong,Simeng Cao,Guanshan Song,Yeheng Peng,Yuanyuan Wang,Yan-Ru Lou,Teemu J Murtola,Yao Wu,Ganjun Yu,Yuan Gao
Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 ( PTEN ) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8 + T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.
研究领域:
肿瘤学
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分子治疗
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药理学
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生物信息学
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纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal for ImmunoTherapy of Cancer
·
2024
·Vol. 12
·期 5
·e008662
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IF 10.3
Gan Xiong,Zhi Chen,Qianwen Liu,Fang Peng,Caihua Zhang,Maosheng Cheng,Rongsong Ling,Shuang Chen,Yu Liang,Demeng Chen,Qimin Zhou
Background CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping immune surveillance in a variety of tumors; however, the underlying mechanisms facilitating immune escape in esophageal squamous cell carcinoma (ESCC) remain enigmatic. Methods We investigated the expression of CD276 in ESCC tissues from patients by using immunohistochemistry (IHC) assays. In vivo, we established a 4-nitroquinoline 1-oxide (4NQO)-induced CD276 knockout (CD276 wKO ) and K14cre; CD276 conditional knockout (CD276 cKO ) mouse model of ESCC to study the functional role of CD276 in ESCC. Furthermore, we used the 4NQO-induced mouse model to evaluate the effects of anti-CXCL1 antibodies, anti-Ly6G antibodies, anti-NK1.1 antibodies, and GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, and immunofluorescence techniques were employed to measure immune cell proportions in ESCC. In addition, we conducted single-cell RNA sequencing analysis to examine the alterations in tumor microenvironment following CD276 depletion. Results In this study, we elucidate that CD276 is markedly upregulated in ESCC, correlating with poor prognosis. In vivo, our results indicate that depletion of CD276 inhibits tumorigenesis and progression of ESCC. Furthermore, conditional knockout of CD276 in epithelial cells engenders a significant downregulation of CXCL1, consequently reducing the formation of neutrophil extracellular trap networks (NETs) via the CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. In addition, overexpression of CD276 promotes tumorigenesis via increasing NETs’ formation and reducing NK cells in vivo. Conclusions This study successfully elucidates the functional role of CD276 in ESCC. Our comprehensive analysis uncovers the significant role of CD276 in modulating immune surveillance mechanisms in ESCC, thereby suggesting that targeting CD276 might serve as a potential therapeutic approach for ESCC treatment.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2020
·Vol. 82
·期 3
·404-411
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IF 1.902
Xiaolong Sun,Xu Wang,Zhenyu Zhao,Jing Chen,Cheng Li,Gang Zhao
Diabetic foot ulcer (DFU) is an invariably common complication of diabetes, characterized by delayed wound healing process and increased inflammation. Evidence has indicated that paeoniflorin exerts an anti-inflammatory effect in diabetic retinopathy. The current work was aimed to investigate the effect of paeoniflorin on inflammation and wound healing in DFU. DFU rat models by streptozotocin and skin biopsy punch, as well as high glucose-treated human immortalized keratinocytes (HaCaT) were established. Levels of blood glucose, wound contraction and proinflammatory cytokine were detected after paeoniflorin administration. Several essential targets associated with the NF-κB and Nod-like receptor protein-3 (NLRP3) signaling pathways were examined. Results showed markedly down-regulation of interleukin (IL)-1β, IL-18 and tumor necrosis factor-alpha in paeoniflorin-treated DFU rats. Paeoniflorin decreased the expression levels of chemokine receptor CXCR2, nuclear NF-κB and p-IκB (Ser36), as well as increased IκB level. Histological analysis and immunostaining showed lower inflammatory cells with decreased NLRP3 and cleaved caspase-1 levels following paeoniflorin treatment. Further in vitro evidence confirmed that paeoniflorin efficiently inhibited NLRP3 and NF-κB-mediated inflammation in DFU by inhibiting CXCR2. These findings are suggestive of greatly attenuated wound inflammation and better wound healing in paeoniflorin-treated DFU rats. Our study demonstrates that paeoniflorin is a potential therapeutic agent for DFU.
研究领域:
药理学
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糖尿病
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炎症研究
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伤口愈合
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Medicina-Lithuania
·
2022
·Vol. 58
·期 12
·1749
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IF 2.948
Aoqi Song,Zhenghua Wu,Wenjuan Zhao,Wenqing Shi,Ru Cheng,Jingjing Jiang,Zhuojun Ni,Han Qu,Xijier Qiaolongbatu,Guorong Fan,Yuefen Lou
Background and Objectives:Hypericum perforatum(HP) is widely used for depressive therapy. Nevertheless, the antidepressant effect and potential mechanism of hyperoside (Hyp), the main active component of HP, have not been determined. Materials and Methods: We performed ultra-performance liquid chromatography–quadrupole-time-of-flight–tandem mass spectrometry (UPLC-Q-TOF-MS/MS) technology to analyze the components in HP. Using data mining and network pharmacology methods, combined with Cytoscape v3.7.1 and other software, the active components, drug-disease targets, and key pathways of HP in the treatment of depression were evaluated. Finally, the antidepressant effects of Hyp and the mechanism involved were verified in chronic-stress-induced mice. Results: We identified 12 compounds from HP. Hyp, isoquercetin, and quercetin are the main active components of HP. The Traditional Chinese Medicine Systems Pharmacology Database (TCMSP), the Analysis Platform, DrugBank, and other databases were analyzed using data mining, and the results show that the active components of HP and depression are linked to targets such as TNF-, IL-2, TLR4, and so on. A potential signaling pathway that was most relevant to the antidepressant effects of Hyp is the C-type lectin receptor signaling pathway. Furthermore, the antidepressant effects of Hyp were examined, and it is verified for the first time that Hyp significantly alleviated depressive-like behaviors in chronic-stress-induced mice, which may be mediated by inhibiting the NLRP1 inflammasome through the CXCL1/CXCR2/BDNF signaling pathway. Conclusion: Hyp is one of the main active components of HP, and Hyp has antidepressant effects through the NLRP1 inflammasome, which may be connected with the CXCL1/CXCR2/BDNF signaling pathway.Keywords:depression;NLRP1 inflammasome;Hypericum perforatum;hyperoside;CXCL1/CXCR2;BDNF
研究领域:
药理学
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神经科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
·
2026
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IF 14
Wenyan Zhao,Xin Zhou,Xingli Zhao,Hao Tian,Yang Su,Shanlan Zhao,Min Liu,Qiao Zhang,Lin Chen,Xiaochen Li,Di Liu,Junxuan Li,Lang Li,Yanhong Wang,Xingtong Li,Jin Yan,Wen Chen,Bing Liu,Chuhong Zhu,Wen Zeng
Renal fibrosis is a common outcome of chronic kidney disease (CKD), forming a fibrotic niche characterized by fibroblast activation and vascular rarefaction. Currently, there are no effective treatment strategies targeting fibrotic niche. Here, we show that chimeric antigen receptor-modified M2 macrophages (CAR-M2) targeting FAP and secreting interleukin (IL)-4 are delivered via an injectable HAMA-CS hydrogel beneath the renal subcapsule and attenuate renal fibrosis while promoting renal revascularization. The single-cell RNA sequencing reveals the heterogeneity and interaction of stroma and endothelial cells (ECs). A fibrosis-related Cxcr2 + EC subset is identified, and its specific depletion effectively mitigates renal fibrosis. Further results reveal that CAR-M2 can release matrix metalloproteinase 2 (MMP2) in close proximity to activate retinoid X receptor alpha (Rxra) in the Cxcr2 + ECs and further triggers its mitochondrial autophagy, leading to apoptosis. Our research provides innovative strategies and proof of principle for the immunotherapy of organ fibrosis.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2016
·
IF 2.551
Ping Huang,Xiaoyan Lu,Baohong Yuan,Tao Liu,Liangcheng Dai,Yunjun Liu,Hui Yin
Astragaloside IV (AS-IV), an active saponin purified from Astragali Radix , has been identified with broad biological and pharmacological activities . In the present study, we continue to explore the potential effect of AS-IV on antibacterial response using an acute E. coli peritoneal infection model. Our findings implied that administration of AS-IV decreases mortality in mice challenged by lethal E. coli infection. The protection of AS-IV was related to promotion of neutrophil extravasation into the peritoneum and bacterial clearance . Toll-like receptor (TLR) activation in neutrophils has been reported to reduce CXCR2 expression and subsequent neutrophil migration. Our data indicated that AS-IV prevented the reduction of CXCR2 expression and neutrophil migration induced by LPS, the activator for TLR4 . Moreover, we found that AS-IV blocks LPS-induced suppression of CXCR2 on neutrophils by inhibiting the expression of G protein-coupled receptor kinase-2 (GRK2), an agonist that regulates desensitization and internalization of chemokine receptors . Taken together, these data propose that AS-IV, through modulating GRK2-CXCR2 signal in neutrophils, offers an essential efficacy on host antibacterial immunity.
研究领域:
免疫学
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药理学
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微生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Jia You,Kun Shi,Xi Yang,Huawei Li,Lingnan Zheng,Yuanfeng Wei,JingYi Xu,Yue Li,Zhiyong Qian,Cheng Yi
Malignant pleural effusion (MPE) is a common complication of advanced malignancy with a median survival of less than 5 months. Intrapleural injection is the main treatment for MPE, but there are problems such as the concentration of drugs not being durable and stable in the thoracic cavity, limiting therapeutic efficacy, rapid metabolism of drugs leading to systemic toxicity, a single mechanism of drug. Esculentoside A (EsA) exhibits multi-targeted effects that are potentially valuable to improve the immunosuppressive microenvironment in the thoracic cavity and suppress the development of MPE. But the toxicity and short half-life of EsA severely limit its use. We have developed an EsA delivery system based on a temperature-sensitive hydrogel (PLEL) for local treatment of MPE by intrapleural injection. The EsA/PLEL hydrogel supported slow-release of EsA and maintained a stable intrathoracic drug concentration, which not only significantly inhibited the progression of MPE and prolonged survival, but also reduced the side effects of EsA. We found that downregulating of CXCL1/CXCL2/CXCL3-CXCR2 axis expression to reduce tumour-associated macrophages (TAMs) infiltration and tumour angiogenesis was a potential molecular mechanism for EsA/PLEL hydrogel to control lung cancer MPE. Therefore, this EsA/PLEL hydrogel delivery system has high potential for intrapleural injection therapy of MPE.
研究领域:
肿瘤学
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药剂学
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分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Shuai Dong,Xingyuan Bai,Bin Chen,Minzhe Fan,Qi Liu,Yubo Zhao,Linsen Li*,Dan Zhu
Background: Panzerina lanata (Lanata) is generally used to treat pustule infection in Inner Mongolia folk medicine and is called “the holy medicine for pustule.” However, the pharmacological mechanism of Lanata in treating pustule infection is still unclear.Aims: This study aimed to investigate the therapeutic effects of Lanata on skin infection and explore the underlying mechanisms.Methods: A skin wound methicillin-resistant Staphylococcus aureus (MRSA) infection mouse model was established to evaluate the healing effect of Lanata on infected wounds. In vitro assays were also conducted to determine the antibacterial activity of Lanata. Flow cytometry and immunohistochemistry were used to dynamically detect the number of neutrophils in the bone marrow, peripheral blood, and MRSA-infected wound. Protein expression in the infected wound skin was detected by a protein chip. Using an air pouch MRSA infection mouse model, the number of neutrophils, reactive oxygen species (ROS) level in neutrophils, and neutrophil extracellular trap (NET) formation were dynamically detected by flow cytometry and immunofluorescence. RNA-seq, RT-qPCR, flow cytometry, ELISA, and CXC chemokine receptor 2 (CXCR2) and P-selectin glycoprotein ligand-1 (PSGL-1) inhibitors were used to explore the mechanism of Lanata in regulating neutrophils.Results: In vitro assays showed that Lanata had no direct antibacterial activity. In skin wound MRSA-infected mouse, Lanata promoted the rapid migration of neutrophils from the bone marrow via peripheral blood to the wound site to eradicate MRSA in the acute stage of infection and accelerate wound healing. Skin protein chip analysis showed that Lanata upregulated CXCR2 and PSGL-1 protein levels in skin wounds. Furthermore, analysis using the air pouch MRSA infection mouse model found that Lanata not only promoted the rapid migration of neutrophils from peripheral blood to the air pouch but also enhanced the activation of neutrophils, including the increase of ROS and the release of NETs, and upregulated the expression of CXCR2, PSGL-1, and myeloperoxidase (MPO) in neutrophils. Inhibition of CXCR2 and MPO significantly attenuated the effect of Lanata on promoting migration and activation of neutrophils.Conclusion: Panzerina lanata resists MRSA infection by promoting migration and activation of neutrophils to rapidly eradicate MRSA.
研究领域:
药理学
·
免疫学
·
微生物学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Gut Microbes
·
2024
·
IF 12.2
Fangfang Chen,Songhe Guo,Yiqiu Li,Yongfan Lu,Le Liu,Shengxin Chen,Jun An,Ge Zhang
The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.
研究领域:
肿瘤学
·
免疫学
·
微生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
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